RESUMO
Although IL-4 induces expulsion of the gastrointestinal nematode parasite, Nippostrongylus brasiliensis, from immunodeficient mice, this parasite is expelled normally by IL-4-deficient mice. This apparent paradox is explained by observations that IL-4 receptor alpha chain (IL-4Ralpha)-deficient mice and Stat6-deficient mice fail to expel N. brasiliensis, and a specific antagonist for IL-13, another activator of Stat6 through IL-4Ralpha, prevents worm expulsion. Thus, N. brasiliensis expulsion requires signaling via IL-4Ralpha and Stat6, and IL-13 may be more important than IL-4 as an inducer of the Stat6 signaling that leads to worm expulsion. Additional observations made in the course of these experiments demonstrate that Stat6 signaling is not required for IL-4 enhancement of IgG1 production and actually inhibits IL-4-induction of mucosal mastocytosis.
Assuntos
Gastroenteropatias/imunologia , Interleucina-13/deficiência , Nippostrongylus/imunologia , Receptores de Interleucina-4/deficiência , Infecções por Strongylida/imunologia , Transativadores/deficiência , Animais , Anticorpos Anti-Helmínticos/biossíntese , Feminino , Gastroenteropatias/parasitologia , Interações Hospedeiro-Parasita/imunologia , Interferon gama/biossíntese , Interleucina-13/genética , Mucosa Intestinal/imunologia , Mastocitose/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Nus , Receptores de Interleucina-4/genética , Fator de Transcrição STAT6 , Transdução de Sinais , Transativadores/genéticaAssuntos
Citocinas/fisiologia , Mucosa Intestinal/patologia , Mastocitose/etiologia , Nippostrongylus , Infecções por Strongylida/imunologia , Animais , Citocinas/genética , Expressão Gênica , Hiperplasia , Mastócitos/imunologia , Mastócitos/patologia , Mastocitose/imunologia , Mastocitose/patologia , Camundongos , Infecções por Strongylida/complicações , Infecções por Strongylida/patologiaRESUMO
Mice infected with the gastrointestinal nematode parasite Nippostrongylus brasiliensis (Nb) develop responses associated with enhanced production of IL-4 (increased serum IgE levels and intestinal mucosal mastocytosis) and IL-5 (tissue and peripheral blood eosinophilia). The antagonistic effects of IFN on IL-4-mediated responses prompted an examination of the effects of IFN on the host response to Nb. Treatment with rIFN-alpha and rIFN-gamma induced a marked increase in parasite egg production (fecundity) in BALB/c mice infected with Nb and delayed intestinal expulsion of adult worms. Treatment with rIFN-alpha or rIFN-gamma also inhibited the rise in peripheral blood eosinophilia that follows inoculation with Nb, and the intensity of pulmonary perivascular tissue eosinophilia. However, Nb-induced increases in serum IgG levels and intestinal mastocytosis were only temporarily delayed by IFN. Induction of endogenous IFN production by injection of fixed Brucella abortus into mice infected with Nb also resulted in an increased worm fecundity and delayed adult worm expulsion. These effects were ablated when mice given Brucella abortus also received injections of neutralizing anti-IFN antibodies. Thus, IFN inhibit host protective immunity to Nb, perhaps by interfering with the production and effects of Th2 cytokines.
Assuntos
Interferon Tipo I/farmacologia , Interferon gama/farmacologia , Nippostrongylus , Infecções por Strongylida/imunologia , Animais , Brucella abortus/imunologia , Eosinofilia/etiologia , Eosinofilia/prevenção & controle , Feminino , Imunoglobulina E/sangue , Indutores de Interferon/farmacologia , Interleucina-4/biossíntese , Interleucina-5/biossíntese , Pulmão/imunologia , Pulmão/patologia , Mastocitose/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Nippostrongylus/imunologia , Nippostrongylus/isolamento & purificação , Proteínas Recombinantes , Infecções por Strongylida/etiologia , Infecções por Strongylida/parasitologiaRESUMO
The role of L3T4+ and Lyt-2+ T cells in protective immunity to Nippostrongylus brasiliensis (Nb) was studied in BALB/c mice that were depleted of either the L3T4+ or Lyt-2+ T cell population by injection with rat mAb specific for the appropriate determinant. Host responses to Nb infection including spontaneous elimination of adult worms, development of intestinal mucosal mast cell hyperplasia and the generation of a polyclonal IgE response were all completely blocked by 0.5 mg anti-L3T4 antibody administered simultaneously with Nb inoculation. However, administration of 0.5 mg of anti-Lyt-2 antibody at the same time and 7 days after inoculation with Nb had no effect on any of these responses. Injection of anti-L3T4 antibody as late as 9 days after Nb inoculation interfered with spontaneous cure of Nb infection and anti-L3T4 antibody injection 11 days after Nb inoculation inhibited serum IgE levels measured on day 13 by 50%. In addition, administration of anti-L3T4 antibody at the time of the peak serum IgE response, 13 days after Nb inoculation, accelerated the decline in serum IgE levels. Injection of previously Nb-infected mice with anti-L3T4 antibody at the time of a second Nb inoculation prevented the development of a secondary IgE response but did not affect immunity to Nb infection based on finding no adult worms in the intestines of these mice. These data indicate that 1) L3T4+ T cells are required for spontaneous cure of Nb infection, development of intestinal mucosal mast cell hyperplasia, and the generation and persistence of an IgE response during primary infection with Nb and 2) L3T4+ T cells are required for a considerable time after inoculation for optimal development of these responses. However, L3T4+ T cells are not required for all protective responses in immune mice. In contrast, our data indicate that considerable depletion of the Lyt-2+ T cell population has no significant effect on either worm expulsion or the generation of serum IgE responses.
Assuntos
Imunoglobulina E/biossíntese , Infecções por Nematoides/imunologia , Nippostrongylus/imunologia , Linfócitos T/imunologia , Animais , Anticorpos Anti-Helmínticos/biossíntese , Antígenos de Diferenciação de Linfócitos T/análise , Antígenos Ly/análise , Memória Imunológica , Mucosa Intestinal/imunologia , Mastócitos/imunologia , Camundongos , Linfócitos T/classificação , Linfócitos T Auxiliares-Indutores/imunologiaRESUMO
Recently, it has been reported that in SJA/9 mice infected with Nippostrongylus brasiliensis there are increased numbers of lymphoid cells positive for surface IgM and IgE (sIgM+ and sIgE+) even though they fail to secrete IgE, that both the sIgM and sIgE on these cells are intrinsic, and that there has been no deletion of genes for the Ig heavy chain constant region in these cells. These observations support a nondeletional model for Ig isotype switching. We have now reexamined the nature of sIgE on sIgE+ spleen and mesenteric lymph node cells of N. brasiliensis-infected SJA/9 mice, and the following observations lead us to believe that this sIgE is cytophilic rather than intrinsic: (i) Only approximately 50% of the N. brasiliensis-infected SJA/9 mice have detectable percentages of sIgE+ lymphoid cells. All mice with detectable sIgE+ lymphocytes have lymphocytes positive for intracytoplasmic IgE (cIgE+) and secrete IgE in vitro, while cIgE+ cells and IgE secretion are absent from N. brasiliensis-infected SJA/9 mice that lack sIgE+ cells. (ii) SJA/9 B lymphocytes have receptors for IgE: expression of these receptors is increased in N. brasiliensis-infected mice that have sIgE+ lymphocytes, but not in infected SJA/9 mice that lack sIgE+ lymphocytes. (iii) Treatment of sIgM+ sIgD+ sIgE+ cells for 1 min with dilute acid removes most sIgE but does not affect expression of sIgM or sIgD. (iv) The removal of mouse IgE from sIgE+ B cells facilitates the binding of exogenous rat IgE. (v) The small amount of sIgE that is reexpressed during a period of in vitro culture after acid treatment is blocked by inclusion of exogenous rat IgE in the culture medium. These observations show that most sIgM+ sIgE+ B cells in N. brasiliensis-infected SJA/9 mice do not express intrinsic sIgE; thus studies using these cells to determine mechanisms of Ig isotype switching are inconclusive.
Assuntos
Linfócitos B/imunologia , Deleção Cromossômica , Imunoglobulina E/genética , Imunoglobulina M/genética , Infecções por Nematoides/imunologia , Animais , Concentração de Íons de Hidrogênio , Imunoglobulina E/análise , Imunoglobulina M/análise , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos , Nippostrongylus , Receptores de Antígenos de Linfócitos B/análise , Receptores de Antígenos de Linfócitos B/genética , Receptores de IgE , Receptores Imunológicos/análise , Baço/imunologiaRESUMO
The IgE response at the cellular level to helminthic infection was studied in BALB/c mice inoculated with the infective larvae of the nematodes Nippostrongylus brasiliensis (Nb) or Trichinella spiralis (Ts) or with the cercariae of the trematode Schistosoma mansoni (Sm). Changes in mesenteric lymph node (MLN) cell number, cell surface(s) IgD, IgM, IgE and Thy-1.2 and intracytoplasmic (c) IgE were recorded. In addition, a comparable study was conducted in rats infected with Nb. At 11 days after infection (DAI) of mice with Nb or Ts, or rats with Nb, there was a 3-fold increase in cell number in the MNL. There was a marked increase in cell number in the MLN of mice infected with Sm at 7 weeks after infection (WAI) and in the spleens of Sm-infected mice at 4 WAI. The percentage of cIgE+ cells increased from undetectable levels in uninfected mice and rats to as high as 0.5-1.3% in the MLN of helminth-infected mice and rats. Analysis of cell surface molecules with a fluorescence activated cell sorter (FACS) showed that Nb and Ts infection induced slight increases in the percentages of B cells and slight decreases in the percentage of T cells. More remarkably, the percentage of sIgE+ cells in the MLN of both Nb- and Ts-infected mice rose from undetectable levels in uninfected mice to 33 and 27%, respectively, at 15 DAI. This rise was stimulated in Ts-infected mice predominantly by adult Ts. In the MLN of Nb-infected rats, the percentage of cells that were sIgE+ was greater than 50% at 15 DAI. However, there was no detectable increase in sIgE+ cells in the spleen and MLN of Sm-infected mice until 5 WAI; peak levels of approximately 20% sIgE+ cells were reached at 8 WAI. Treatment of MLN cells from mice infected with Nb, Ts or Sm and rats infected with Nb, with pH 4.0 acetate buffer for 1 min (acid treatment) removed all detectable sIgE from greater than 90% of the sIgE+ cells, but did not remove sIgD or sIgM from cells with these surface isotypes. The effect of acid treatment on sIgE was similar even after a secondary infection of mice or rats with nematode larvae. These data show that helminthic infection, in general, is a potent stimulator of the IgE system at the cellular level and that almost all of the sIgE+ cells that arise have acquired cytophilic sIgE.
Assuntos
Imunoglobulina E/biossíntese , Linfócitos/imunologia , Infecções por Nematoides/imunologia , Esquistossomose/imunologia , Triquinelose/imunologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nippostrongylus/imunologia , Ratos , Ratos Endogâmicos , Schistosoma mansoni/imunologia , Trichinella/imunologiaAssuntos
Linfócitos B/imunologia , Imunoglobulina E/biossíntese , Infecções por Nematoides/imunologia , Nippostrongylus/imunologia , Animais , Compartimento Celular , Membrana Celular/imunologia , Citoplasma/imunologia , Relação Dose-Resposta Imunológica , Feminino , Linfonodos/imunologia , Masculino , Camundongos , Coelhos , Receptores de Antígenos de Linfócitos B/análise , Baço/imunologiaAssuntos
Anticorpos Anti-Idiotípicos/imunologia , Linfonodos/imunologia , Linfocinas/biossíntese , Infecções por Nematoides/imunologia , Animais , Linfócitos B/imunologia , Feminino , Imunoglobulina D/imunologia , Imunoglobulina E/imunologia , Imunoglobulina M/imunologia , Nippostrongylus/imunologia , RatosAssuntos
Linfócitos B/imunologia , Imunoglobulina E/biossíntese , Linfonodos/imunologia , Linfócitos/imunologia , Infecções por Nematoides/imunologia , Animais , Células da Medula Óssea , Células Cultivadas , Feminino , Ativação Linfocitária , Nippostrongylus , Ratos , Receptores de Antígenos de Linfócitos B , Baço/imunologiaAssuntos
Linfócitos B/imunologia , Imunoglobulina E/biossíntese , Imunoglobulina M , Infecções por Nematoides/imunologia , Animais , Células da Medula Óssea , Diferenciação Celular , Sistema Livre de Células , Células Cultivadas , Dactinomicina/farmacologia , Feminino , Linfonodos/imunologia , Nippostrongylus , Pactamicina/farmacologia , Ratos , Receptores de Antígenos de Linfócitos BRESUMO
Normal rat bone marrow cells incubated with serum or lymph from Nippostrongylus brasiliensis (Nb)-infected rats showed an increase in the proportion of IgE-bearing cells in culture. This effect was produced in a similar fashion by cell-free supernatants (CFS) from cultures of mesenteric lymph node cells obtained from Nb-infected rats. The action of CFS on bone marrow cells appeared to be specific for the generation of IgE-bearing cells since the proportion of IgM-bearing cells in the culture did not change. The IgE-bearing cells in bone marrow cell cultures consisted of small lymphocytes, blast cells, and mast cells, and the addition of CFS to the cultures predominantly increased the number of IgE-bearing blast cells. CFS was also effective in increasing the proportion of IgE-bearing small lymphocytes in cultures of normal mesenteric lymph node cells. Removal of IgE in CFS by an anti-IgE immunosorbent did not affect the ability of CFS to generate IgE-bearing cells. The factor(s) in CFS responsible for this activity was shown to migrate with serum beta-globulins in zone electrophoresis and to possess a molecular size of between 10(4) and 2 X 10(4) m.w. The ability of CFS to generate IgE-bearing cells was diminished by treatment with the enzymes trypsin and ribonuclease A, but was unaffected by chymotrypsin.